Compositions and methods for the delivery of agents

ABSTRACT

The present invention relates to methods and compositions for the delivery of cosmetics and medicants. In some embodiments, the invention relates to compositions comprising both hydrophobic and hydrophilic polymers. In preferred embodiments, the invention relates to the delivery of peptides, small molecules and other bioactive compounds using the compositions and methods disclosed herein.

This application is a continuation application of, and claims priorityto, U.S. application Ser. No. 12/933,337, filed Nov. 4, 2010, whichissued as U.S. Pat. No. 9,233,080 on Jan. 12, 2016, which is the U.S.National stage filing under 35 U.S.C. § 371 of, and claims priority to,International Application No. PCT/US09/01910, filed on Mar. 26, 2009,now abandoned, which claims priority to U.S. provisional ApplicationSer. No. 61/040,016, filed Mar. 27, 2008, each of which is hereinincorporated by reference.

FIELD OF THE INVENTION

The present invention relates to methods and compositions for thedelivery of cosmetics and medicants. In some embodiments, the inventionrelates to compositions comprising hydrophilic polymers, as well ascompositions comprising both hydrophobic and hydrophilic polymers. Inpreferred embodiments, the invention relates to the delivery ofvitamins, peptides, small molecules, medicants and other bioactivecompounds, whether alone, in mixtures, or encapsulated (e.g.encapsulated in microspheres or nanospheres) using the compositions andmethods disclosed herein.

BACKGROUND OF THE INVENTION

Cosmetics and skin care compositions are among the world's most widelyresearched and commercialized commodities. The significant cost of manyof these compositions necessitates that they be delivered to a subjectin an effective manner. However, the physical and/or chemicallimitations as well as the ease and safety of many traditional deliverysystems obviates their use in the administration of many dermallyapplied entities, particularly in view of their rapid development andimprovement as well as their ever-increasing demand worldwide. Thus,there is a need to identify compositions that effectively facilitate thedelivery of cosmetics and skin care compositions.

SUMMARY OF THE INVENTION

The present invention relates to methods of making transdermal andtopical delivery devices, as well as methods and compositions for thedelivery of agents, including cosmetic agents (e.g. vitamins, dermalfillers, botox, etc.) and medicants. In some embodiments, the inventionrelates to compositions comprising hydrophilic polymers, as well ascompositions comprising both hydrophobic and hydrophilic polymers. Inpreferred embodiments, the invention relates to the delivery ofvitamins, peptides, small molecules and other bioactive compounds,whether alone, in mixtures, or encapsulated (e.g. encapsulated inmicrospheres or nanospheres), using the compositions and methodsdisclosed herein. In further embodiments, the invention relates tocompositions comprising clay and comprising a bioactive agent for thetreatment of skin diseases and disorders. Cosmetic treatment (e.g.reduce wrinkles) is also contemplated.

In one embodiment, the present invention contemplates a dissolving or“disappearing” (e.g. the outline of the material and the material itselfbecomes invisible as the material transforms from solid, or semi-solid,to liquid) film or patch for use on the skin to deliver compounds (e.g.vitamins, peptides, drugs, etc.). In one embodiment, the dissolving filmor patch comprises hydrophilic polymer fibers, e.g. a polymer fibermatrix that is porous, but mechanically strong enough to apply to theskin without tearing. Structural materials for the patch are selected inorder to achieve desired patch dissolution rate on the skin (e.g. lessthan 10 seconds, approximately 10 seconds, 10 minutes, 10 hours, 10days). The more hydrophilic, the faster (e.g. 1-20 seconds) thedissolution; conversely, the more hydrophobic, the slower (minutes tohours to days) the dissolution. In one embodiment, a polymer (or mix ofpolymers) is employed in a structural portion of the patch, whichdissolves on the skin at a pre-determined rate. In a preferredembodiment, the skin is pretreated to make it moist or wet (e.g. with alight spray or aerosol, comprising water and other optionalingredients). In one embodiment, one or more active ingredients areincorporated or trapped within the matrix. For example, the presentinvention contemplates embodiments wherein the active ingredients are a)incorporated into the structural backbone of the fibers (or simplyabsorbed on the fibers) and/or b) integrated into (or trapped within)the voids of the structure. The amount which goes into a) or b) can becontrolled (e.g. depending on the nature of the fibers, the porosity ofthe matrix, the interaction of the fibers with the active ingredients,and the like). Where microspheres or nanospheres are employed, theamount which goes in may depend on how fast and thoroughly the spheresdissolve, as well as the content of the spheres. In this way, thepresent invention contemplates, in one embodiment, 1) burst release (ofactive ingredients) out of the voids followed by 2) slower release outof the fibers as they dissolve.

The present invention relates to a novel method of manufacturing atransdermal drug delivery matrix and alleviates many of the difficultiescurrently faced during the preparation of transdermal drug deliverymatrices. In addition, the present method of manufacture yields uniformcompositions of transdermal polymer mixtures containing an active agent,prepared without using large quantities of solvents, and without loss ofthe active agent due to exposure to temperature variations. Due to theirextreme porosity the self-dissolving transdermal matrices prepared bythese methods perform better in transdermal devices and show greaterflux of active agent. 100% flux of the drug out of self-dissolvingmatrices prepared by the method of the present invention can bedemonstrated. As a result of the improved performance, less active agentcan be utilized during the manufacturing process.

Thus, in contrast to typical skin patches, where only a small amount(1-10%) of active ingredient is employed and only a portion (10-50%) isdelivered, the present invention contemplates films or patches whereinthe active ingredient is the major component of the patch composition(e.g. greater than 50%, more preferably at least 70%, still morepreferably at least 80%, and most preferably between 80 and 95%) and thevast majority of the active ingredient (80-100%) is delivered into theskin. In one embodiment, the preferred film or patch should incorporate(or carry) the active ingredient(s) without involvement of softeners,plasticizers and preservatives.

In one embodiment, the present invention also contemplates a film orpatch wherein only a portion dissolves or “disappears” quickly (secondsto minutes). For example, the dissolving portion is hydrophilic, whereasthe stable portion (hours to days) is hydrophobic.

The films and patches of the present invention can be used alone or withother modes of delivery, including but not limited to microneedles,iontophoresis, electroporation, and the like. For example, in oneembodiment, microneedles (discussed more below) are applied to the skinand the film or patch is placed on top of the microneedles (which may bepre-treated to facilitate the dissolution of the patch and release ofactive ingredients) so that compounds (including high molecular weightcompounds) are delivered more readily (and more deeply) into the skin.In another embodiment, the film or patch is part of an iontophoresispatch (discussed more below).

The films and patches of the present invention can be used alone or with“activators.” For example, in a preferred embodiment, the skin ispretreated to make it moist or wet (e.g. with a light spray or aerosol,comprising water and other optional ingredients). Such optionalingredients include, but are not limited to: NaPCA [availablecommercially as Twinlab NaPCA with the following ingredients: Purifiedwater, NaPCA (the sodium salt of pyrrolidone carboxylic acid),eucalyptus, ethanol, monolaurin (the principal antimicrobial factor inmother's milk)]; isopropyl alcohol; Beta Glucan [which is available asBeta-glucan, with 1,3- and 1,6-glucose links, which can be isolated froma variety of fungi such as shiitake (Lentinus edodes) and maitake(Grifola frondosa) mushrooms, or from yeast cell walls includingbrewers' and bakers' yeasts (of the genus Saccharomyces), and from oatand barley bran]; Butylene glycol; hyluronic acid and the like (all ofwhich can be combined together in various combinations).

In one embodiment, the present invention contemplates formulating filmsand patches (and similar media) using polymers that are capable ofabsorbing water (hydroscopic or hydrophilic) as well as capable ofabsorbing oil when diluted in a solvent. In one embodiment, the activeingredients) is mixed in or formulated with the matrix, and the active(whether based on water, oil or solids) is released and eluted/deliveredwhen the media is applied to humid (moist or wet) tissue.

In some embodiments, the invention relates to a composition (e.g. a skincare composition) comprising a first layer under a second layer, saidfirst layer comprising a biomaterial (including but not limited to amaterial selected from the group consisting of collagen, cellulose andalgenate, as well as nanospheres thereof), said second layer comprisingpolymeric fibers, said fibers selected from the group consisting ofmicrofibers and nanofibers. In a preferred embodiment, said second layercomprises electrospun microfibers (or nanofibers) In furtherembodiments, said polymeric microfibers (or nanofibers) comprises ahydrophilic polymer. In still further embodiments, said polymericmicrofibers (or nanofibers) comprises a hydrophobic polymer. Inadditional embodiments, said polymeric microfibers (or nanofibers)possess adhesive properties upon wetting. In additional embodiments,said polymeric microfibers (or nanofibers) can be impregnated with asolution of active ingredient(s) for controlled or sustained delivery ofactive ingredient(s). In some embodiments, said active ingredient(s) isstored dry (e.g. as a solid formulation) and is activated upon wettingof said polymeric microfibers (or nanofibers) so as to form a solutionof the active ingredient(s) in the microfiber (or nanofiber) forcontrolled or sustained delivery of the active ingredient(s). In furtherembodiments, said polymeric microfibers (or nanofibers) form aninvisible film upon wetting that further dissolves upon additionalwetting. In still further embodiments, said polymeric microfibers (ornanofibers) containing active ingredient(s) are coated onto said firstlayer so as to form said second layer.

Today's available skincare plasters can have difficulty adhering to asweating skin surface in connection with sports or burns. That is tosay, they tend to slide away or off the skin, which limits the time forthe active drug in the plaster to activate. By adding a first top layerof PVP fibers, in one embodiment, the sweat is absorbed and the activedrug is accelerated.

It is not intended that the composition be limited by the nature of thepolymer(s) used for the microfibers (or nanofibers). A variety ofpolymers can be used. Indeed, multiple (different) polymers can be usedtogether or separately. In a preferred embodiment, the composition ismade using both hydrophobic and hydrophilic polymers (see FIG. 1). Whena variety of polymers are used together (e.g. multiple kinds of polymersin the second layer), this allows for “tagging” each fiber withdifferent active ingredients, allowing for a significant scope offunctionality.

Is not intended that the present invention be limited by the nature ofthe biomaterial. In a preferred embodiment, the biomaterial isabsorbent, and even highly absorbent. In such an embodiment, the presentinvention contemplates combining highly absorbent “sponges” with solidmicrofiber (or nanofiber) platforms to obtain advantages over otherdelivery technologies.

It is also not intended that the present invention be limited by thenumber of layers. Single, double, triple layer (or more) deliverydevices are contemplated. The present invention, in one embodiment,contemplates a method for fabricating a three layer matrix (FIG. 5C),wherein three layers are electrospun from three different solutions viathree tips on to one and same collector. In one embodiment, the processbegins by adding first layer to the collector, then continuing by addingthe first combined with the second layer, and then gradually removingthe first layer while continuing with a second layer alone, thencontinuing with a combined second and third layer, and then graduallyremoving the second layer and continuing with a third layer. In oneembodiment, the present invention contemplates a three-layer matrix,said matrix comprising thrombin in one of the three layers.

It is not intended that the present invention be limited by the methodby which active agent is added. In some embodiments, the active agent isadded in dry form (this permits the use of agents which are not stable,or as stable, in solution). In some embodiments, the agent is added insolution and then allowed to dry. In some embodiments (FIG. 3), thepolymeric fibers are treated with water prior to adding the activeagent(s). In some embodiments, the active agent(s) is sprayed onto theskin (e.g. in a mist, spray or aerosol) and the film or patch is placedon top of the area that contains the agent, whereupon the film or patchdissolves and facilitates the delivery of the active agent (even thoughthe active agent was not formulated into, onto, or within the film orpatch).

In one embodiment, the skin patch comprising polymeric fibers (an one ormore active ingredients) is applied to the skin without pre-wetting theskin. This embodiment allows for “on command” delivery. When delivery isdesired, the patch (or portion thereof) is sprayed (or otherwisecontacted) with water (or an aqueous solution containing such optionalingredients as described herein) in order to trigger dissolution anddelivery (e.g. in a bolus) of the active ingredient(s). A variety ofactive ingredients can be delivered in this manner. Particularlypreferred actives for this approach include agents that reduce pain, andagents (e.g. nicotine) that reduce the desire for addictive (e.g.smoking) behavior or compulsive behavior. In one embodiment, agents thatcombat depression are contemplated in this mode of delivery. In anotherembodiment, agents that combat fatigue (e.g. for large equipmentoperators, truck drivers, train engineers, etc.) are contemplated inthis mode of delivery.

It is also not intended that the present invention be limited by thenature or number of the active agent(s). In one embodiment, the presentinvention contemplates co-formulation of incompatible drugs (e.g. drugswhose characteristics make it difficult to co-formulate in a solution)which is possible because of the fiber matrix. In one embodiment,combination of drugs and cosmetic active ingredients are used in thesame patch; for example, if there is a drug that irritates the skin, thepresent invention contemplates in one embodiment co-formulating asoothing cosmetic ingredient that will repair and sooth the skin afterdrug is delivered. In one embodiment, the present invention contemplatesagents that are currently injected into the skin (e.g. botox, which canbe made recombinantly as described in U.S. Pat. No. 5,919,665, herebyincorporated by reference); by using the patch, such injections are notneeded (i.e. botox can be delivered without injections). In oneembodiment, the present invention contemplates utilizing the fibermatrix to stabilize volatile drugs. In one embodiment, vitamins areobtained as fluids, water or oil or as solid crystals. In anotherembodiment, peptides, whether ribosomal and non-ribosomal (e.g.glutathione), are obtained in water solutions or as solids, or powder.In another embodiment, antibacterial and/or anti-inflammatoryformulations are employed. Any number of active agents that induce adesired local or systemic effect may be used in the drug deliverydevices manufactured by the method of the present invention. Inparticular, any compound that is suitable for transdermal administrationmay be employed. Active agents include, but are not limited to,compounds that may be classified as medicines, organic and inorganicdrugs, hormones, nutrients, vitamins, food supplements, herbalpreparations, and other agents that might benefit a human or animal. Ingeneral, such classifications include, but are not limited to, ACEinhibitors, adrenergics and anti-adrenergics, alcohol deterrents (forexample, disulfiram), anti-allergies, anti-anginals, anti-arthritics,anti-infectives (including but not limited to antibacterials,antibiotics, antifungals, anthelminthics, antimalarials and antiviralagents), analgesics and analgesic combinations, local and systemicanesthetics, appetite suppressants, antioxidants, anxiolytics,anorexics, antiarthritics, anti-asthmatic agents, anticoagulants,anticonvulsants, antidiabetic agents, antidiarrheals, anti-emetics,anti-epileptics, antihistamines, anti-inflammatory agents,antihypertensives, antimigraines, antinauseants, antineoplastics,antioxidants, antiparkinsonism drugs, antipruritics, antipyretics,antirheumatics, antispasmodics, antitussives, adrenergic receptoragonists and antagonists, anorexics, appetite suppressants, breathfreshening agents (including but not limited to peppermint oil,spearmint oil, wintergreen oil and menthol), cardiovascular preparations(including anti-arrhythmic agents, cardiotonics, cardiac depressants,calcium channel blockers and beta blockers), cholinergics andanticholinergics, contraceptives, cough and cold preparations,diuretics, decongestants, growth stimulants, herbal preparations,hormones including but not limited to androgens, estrogens andprogestins, steroids and corticosteroids, hypnotics, immunizing agents,immunomodulators, immunosuppresives, muscle relaxants,neurologically-active agents including anti-anxiety preparations,antidepressants, antipsycotics, psychostimulants, sedatives andtranquilizers, sore throat medicaments, sympathomimetics, vaccines,vasodilators, vasoconstrictors, vitamins, xanthine derivatives andcombinations thereof.

The amount of active agent incorporated will vary, depending on theactive agent chosen, the potency of the compound, the intended dosage,the group of individuals undergoing treatment, the particularindication, and the like. Such amounts are easily determined by one ofordinary skill in the art (see, for example, Volume 18 of Drugs and thePharmaceutical Sciences, entitled “Dermatological Formulations:Percutaneous Absorption” (1983) Marcel Dekker, Inc. and the Handbook ofPressure Sensitive Adhesive Technology, 2nd Edition (1989) Van Nostrand,Reinhold).

Additional representative active agents include, by way of example andnot for purposes of limitation, bepridil, diltiazen, felodipine,isradipine, nicardipine, nifedipine, nimodipine, nitredipine, verapamil,dobutamine, isoproterenol, carterolol, labetalol, levobunolol nadolol,penbutolol, pindolol, propranolol, solatol, timolol, acebutolol,atenolol, betaxolol, esmolol, metoprolol, albuterol, bitolterol,isoetharine, metaproterenol, pirbuterol, ritodrine, terbutaline,alclometasone, aldosterone, amcinonide, beclomethasone dipropionate,betamethasone, clobetasol, clocortolone, cortisol, cortisone,corticosterone, desonide, desoximetasone, 11-desoxycorticosterone,11-desoxycortisol, dexamethasone, diflorasone, fludrocortisone,flunisolide, fluocinolone, fluocinonide, fluorometholone,flurandrenolide, halcinonide, hydrocortisone, medrysone,6a-methylprednisolone, mometasone, paramethasone, prednisolone,prednisone, tetrahydrocortisol, triamcinolone, benoxinate, benzocaine,bupivacaine, chloroprocaine, cocaine, dibucaine, dyclonine, etidocaine,isobutamben, lidocaine, mepivacaine, pramoxine, prilocaine, procaine,proparacaine, tetracaine, zolamine hydrochloride, alfentanil, choroform,clonidine, cyclopropane, desflurane, diethyl ether, droperidol,enflurane, etomidate, fentanyl, halothane, isoflurane, ketaminehydrochloride, mepridine, methohexital, methoxyflurane, morphine,propofol, sevoflurane, sufentanil, thiamylal, thiopental, acetominophen,allopurinol, apazone, aspirin, auranofin, aurothioglucose, colchicine,diclofenac, diflunisal, etodolac, fenoprofen, fllurbiprofen, gold sodiumthiomalate, ibuprofen, indomethacin, ketoprofen, meclofenamate,mefenamic acid, meselamine, methyl salicylate, nabumetone, naproxen,oxyphenbutazone, phenacetin, phenylbutazone, piroxican, salicylamide,salicylate, salicylic acid, salsalate, sulfasalazine, sulindac,tolmetin, acetophenazine, chlorpromazine, fluphenazine, mesoridazine,perphenazine, thioridazine, trifluorperazine, triflupromazine,disopyramide, encainide, flecainide, indecanide, mexiletine, moricizine,phenytoin, procainamide, propafenone, quinidine, tocainide, cisapride,domperidone, dronabinol, haloperidol, metoclopramide, nabilone,prochlorperazine, promethazine, thiethylperazine, trimethobenzamide,buprenorphine, butorphanol, codeine, dezocine, diphenoxylate, drocode,hydrocodone, hydromorphone, levallorphan, levorphanol, loperamide,meptazinol, methadone, nalbuphine, nalmefene, nalorphine, naloxone,naltrexone, oxybutynin, oxycodone, oxymorphone, pentazocine,propoxyphene, isosorbide dinditrate, nitroglycerin, theophylline,phenylephrine, ephidrine, pilocarpine, furosemide, tetracycline,chlorpheniramine, ketorolac, ketorolac tromethamine, bromocriptine,guanabenz, prazosin, doxazosin, flufenamic acid, benzonatate,dextromethorphan hydrobromide, noscapine, codeine phosphate,scopolamine, minoxidil, combinations of the above-identified activeagents, and pharmaceutically acceptable salts thereof.

Other representative agents include, but are not limited to,benzodiazepines, such as alprazolan, brotizolam, chlordiazepoxide,clobazam, clonazepam, clorazepate, demoxepam, diazepam, flumazenil,flurazepan, halazepan, lorazepan, midazolam, nitrazepan, nordazepan,oxazepan, prazepam, quazepan, temazepan, triazolan, pharmaceuticallyacceptable salts thereof, and combinations thereof; anticholinergicagents such as anisotropine, atropine, belladonna, clidinium,cyclopentolate, dicyclomine, flavoxate, glycopyrrolate, hexocyclium,homatropine, ipratropium, isopropamide, mepenzolate, methantheline,oxyphencyclimine, pirenzepine, propantheline, telezepine, tridihexethyl,tropicamide, combinations thereof, and pharmaceutically acceptable saltsthereof; estrogens, including but not limited to, 17p-estradiol (orestradiol), 17a-estradiol, chlorotrianisene, methyl estradiol, estriol,equilin, estrone, estropipate, fenestrel, mestranol, quinestrol,estrogen esters (including but not limited to estradiol cypionate,estradiol enanthate, estradiol valerate, estradiol-3-benzoate, estradiolundecylate, and estradiol 16,17-hemisuccinate), ethinyl estradiol,ethinyl estradiol-3-isopropylsulphonate, pharmaceutically acceptablesalts thereof, and combinations thereof; androgens such as danazol,fluoxymesterone, methandrostenolone, methyltestosterone, nandrolone,nandrolone decanoate, nandrolone phenproprionate, oxandrolone,oxymetholone, stanozolol, testolactone, testosterone, testosteronecypionate, testosterone enanthate, testosterone propionate,19-nortestosterone, pharmaceutically acceptable salts thereof, andcombinations thereof; and progestins such as cingestol, ethynodioldiacetate, gestaclone, gestodene, bydroxyprogesterone caproate,levonorgestrel, medroxyprogesterone acetate, megestrol acetate,norgestimate, 17-deacetyl norgestimate, norethindrone, norethindroneacetate, norethynodrel, norgestrel, desogestrel, progesterone,quingestrone, tigestol, pharmaceutically acceptable salts thereof, andcombinations thereof.

In another embodiment, nicotine is added into the hydrophilic fibers asto instantly release as a bolus to meet the nicotine demands of asmoker. In a yet another embodiment, antibacterial, antibiotic, paincontrol, scar-reduction formulations are employed. In still anotherembodiment, a multi layer matrix releases thrombin, such as RECOTHROM™manufactured by Zymogenetic Inc, or Tisseel (a two component fibrinbiomatrix manufactured by Baxter Inc.) so as to stop diffused bleeding.In this latter embodiment, it is preferred that thrombin is on onesurface, while a high molecular weight Hyaluronic Acid (e.g.manufactured by NovoZymes) is used on the upperside surface hinderingfriction and tissue adherence.

In some embodiments, the invention relates to a method for administeringa compound, comprising: a) providing i) a subject, and ii) a skin carecomposition according to the above (e.g. polymeric microfibers ornanofibers over a biomaterial, with one or more active agents) and b)administering said skin care composition to said subject (e.g. bybringing said first layer or second layer in contact with said subject).In further embodiments said composition is administered topically. Insome embodiments, said composition is administered transdermally. Infurther embodiments, said compound or agent is a peptide, vitamin,organic acid, oil or medicant. In additional embodiments, said subjectexhibits symptoms associated with or is suspected of having a skindisorder (or is at risk for such a disorder). In some embodiments, saidskin disorder is selected from the group consisting of acne, bed sores,rash, dry skin, dermal abrasions, dermatitis, sunburn, scars,hyperkeratosis, granuloma and skin ulceration. In one embodiment,protectants are administered via the patch to protect from sunburn (e.g.block UV). In further embodiments, said vitamin is selected from thegroup consisting of vitamin C, vitamin A, vitamin E, vitamin K andvitamin B complex. In still further embodiments, said organic acid ishyaluronic acid, and preferably low molecular weight (e.g. 50 kD)hyaluronic acid (which can be obtained from a variety of sources,including Degussa in Germany). In one embodiment, the present inventioncontemplates utilizing methods and compositions to stabilize vitaminsand/or improve delivery through the skin. Methods and compositions forstabilizing vitamins are described in WO/2003/011233 (and in patentscited within this PCT application), all of which are hereby incorporatedby reference. In one embodiment, vitamin derivatives are employed (e.g.retinoic ester is a derivative of vitamin A). In one embodiment,encapsulated vitamins are employed, including but not limited toencapsulated vitamin C available from Nanohybrid Co. (Seoul, Korea). Inanother embodiment, agents are encapsulated using the methodology ofSol-Gel Technologies Ltd.

In some embodiments, the invention relates to a composition (e.g. a skincare composition) comprising a first layer under a second layer (FIG.5B), said first layer comprising a first polymer (including but notlimited to hydrophilic synthetic polymers such as PVP, or other “skinfriendly” polymers), said second layer comprising a second polymer. In apreferred embodiment, said second polymer comprises electrospunpolymeric microfibers (or nanofibers). In some embodiments, said secondlayer further comprises one or more active ingredients. In someembodiments, said first layer comprises one or more active ingredients(and the second layer lacks active agents, maintains its structuralintegrity, and serves simply as an occlusive layer). In yet otherembodiments, both said first and second layer comprise one or moreactive ingredients (e.g. both contain the same active agents, or eachcontain different active agents). In one preferred embodiment, bothlayers contain the same active agent, wherein the release kinetics aredifferent (for example, where the first layer is PVP, contact with theskin typically causes the PVP to dissolve, or partially dissolve,thereby releasing active agent in a “burst”—while the second layer ismore stable and provides for sustained release, and longer term releaseif encapsulated in nanospheres). In preferred embodiments, both thefirst and second layers comprise electrospun polymers, such that saidpolymers are microfibers (or nanofibers). In some embodiments, saidactive ingredient(s) is stored dry (e.g. as a solid formulation) in thesecond layer and is activated upon wetting of said polymeric microfibers(or nanofibers) so as to form a solution of the active ingredient(s) inthe microfiber (or nanofiber) for controlled or sustained delivery ofthe active ingredient(s). In further embodiments, said polymericmicrofibers (or nanofibers) of said first layer form an invisible filmupon wetting that further dissolves upon additional wetting.

While electrospun matrices are preferred, some active agents (e.g.medication cocktails) cannot tolerate the electrical field used inelectrospinning. Therefore, in one embodiment, the present inventioncontemplates utilizing ultrasonic coating. In one embodiment, bothtechniques are employed, i.e. at least one nano electro spinning tiptogether with at least one ultra-sonic nozzle (e.g. from SONO-TEKCorporation) which let the spheres fall on to the drum, the collector.

In some embodiments, the invention relates to a method for administeringa compound, comprising: a) providing i) a subject, and ii) a skin carecomposition according to the above (e.g. first and second layers, eachcomprising polymeric microfibers or nanofibers, with one or more activeagents in one or both layers) and b) administering said skin carecomposition to said subject (e.g. by bringing said first layer or secondlayer in contact with said subject). In further embodiments saidcomposition is administered topically. In some embodiments, saidcomposition is administered transdermally, or subcutaneously betweentissues (e.g. by surgical intervention).

Again, it is not intended that the present invention be limited by theparticular polymer used. Table 1 provides (non-limiting) examples ofuseful polymers for various embodiments of the present invention. In oneembodiment, the film or patch can be completely made out of ingredientsthat are recognized as cosmetically active or at least very skinfriendly (e.g. a structural portion of the patch can be made out ofhyaluronic acid polymer, or aloe vera polymer or any other naturalpolymer).

In one embodiment, the present invention contemplates using aliphaticpolyether polyurethane as a polymer to make the fiber matrices for afilm or patch to deliver active ingredient(s). TECOGEL® 200 is acommercially available (manufactured by Thermedics Polymer Products,Wilmington, Mass.) form of aliphatic polyether polyurethane that iscapable of absorbing 200% of its weight in water. Similarly availableare TECOGEL® 500, which is capable of absorbing 500% of its weight inwater, and TECOGEL® 2000, which is capable of absorbing 2000% of itsweight in water. Other TECOGEL® polymers can be engineered with waterabsorption less than 200% and more than 2000% and could be utilized withthe present invention for specific applications. Medical grade aliphaticpolyether based hydrogel TPUs are available from Lubrizol under the nameTecophilic® TG-500 or TG-2000, which can absorb water up to 900% of theweight of the dry resin.

In one embodiment, the present invention contemplates a skin patchcomprising a matrix of fibers and one or more active ingredients,wherein said fibers are hydrophilic fibers capable of becoming aninvisible film upon wetting that further dissolves completely (i.e. nosolid structural portion is visible to the eye) in less than one minute(e.g. less than 30 seconds, or more preferably between 1 and 20seconds). In a preferred embodiment, said matrix lacks hydrophobicfibers. In a particularly preferred embodiment, said matrix is made(e.g. exclusively) of electrospun PVP fibers. Again, it is not intendedthat the present invention be limited by the nature or number of activeingredients (e.g. said active ingredient is a cosmetic, peptide,vitamin, organic acid, oil or medicant). The present inventioncontemplates using such a patch or film to deliver actives into theskin. Thus, in one embodiment, the present invention contemplates amethod for delivering an active ingredient into the skin: a) providingi) a subject (who may healthy or may have a disorder), and ii) the skinpatch described above; and b) administering said skin patch to saidsubject under conditions such that said active ingredient is deliveredinto the skin. In one embodiment, said conditions of step b) comprisepre-wetting skin of said subject prior to applying said skin patch. Inone embodiment, said pre-wetting comprises spraying an aqueous solutiononto said skin (e.g. wherein said spraying results in a mist oraerosol).

As noted above, the active ingredients need not be included in the patch(or at least some actives can be outside the patch, whether the patchhas additional actives or not). Thus, in one embodiment, the presentinvention contemplates a method for delivering an active ingredient intothe skin: a) providing a subject (who may be healthy or who may have adisorder), a solution comprising an active ingredient; and a skin patchcomprising electrospun hydrophilic fibers; b) pre-wetting skin of saidsubject with said solution; and c) administering said skin patch to saidsubject under conditions such that said active ingredient is deliveredinto the skin. Again, said pre-wetting comprises spraying said solutiononto said skin (e.g. wherein said spraying results in a mist oraerosol).

The present invention also contemplates kits comprising the variousfilms or patches described herein. Thus, in one embodiment, the presentinvention contemplates a kit, comprising a pre-wetting solution, and askin patch, said skin patch comprising electrospun hydrophilic fibers.In one embodiment, said pre-wetting solution comprises an activeingredient. In one embodiment, said patch comprises an activeingredient. In one embodiment, the kit further comprises instructionsfor pre-wetting skin and applying said patch under conditions to form aninvisible film that dissolves completely in less than one minute (e.g.less than 30 seconds, or more preferably between 1 and 20 seconds).

BRIEF DESCRIPTION OF THE DRAWINGS

For a more complete understanding of the features and advantages of thepresent invention, reference is now made to the detailed description ofthe invention along with the accompanying figures.

FIG. 1 shows a micrograph of one embodiment of the present invention, inwhich a composition comprised of a hydrophobic fiber (1) and ahydrophilic fiber that has been impregnated with a bioactive ingredient(2).

FIG. 2 shows a micrograph of one embodiment of the present invention, inwhich a composition comprised of a hydrophobic fiber (1), an adheringmolecule nanosphere (2) and a hydrophilic fiber that has beenimpregnated with a bioactive ingredient (3).

FIG. 3 shows a schematic depicting the compilation of the presentinvention, in which both a hydrophobic and a hydrophilic polymer areintegrated. The resulting composition is ordered under aqueousconditions followed by incorporation of the bioactive ingredient(s).

FIG. 4 shows a schematic comparing traditional transdermal devices(which has a great deal of structure compared to active ingredients)with one embodiment of the patch according to the present invention(wherein the structural portion can represent as less than 50%, morepreferably less than 30%, and as little as approximately 20%, of totalpatch volume) which illustrates a 3-dimensional, single layer matrix,into which multiple functions are integrated by modulating formulationsand processing conditions during the patch manufacturing. For instancethe uppermost section of the patch (the equivalent of backing layer intraditional devices) features properties that enable desired level ofpatch occlusiveness, or no occlusive properties at all. Adhesiveproperties of the lower patch section that contacts skin are controlledin a similar fashion.

FIG. 5 shows a schematic depicting single layer (A), two layer (B), andthree layer (C) devices according to the teachings herein.

DEFINITIONS

To facilitate the understanding of this invention, a number of terms aredefined below. Terms defined herein have meanings as commonly understoodby a person of ordinary skill in the areas relevant to the presentinvention. Terms such as “a”, “an” and “the” are not intended to referto only a singular entity, but include the general class of which aspecific example may be used for illustration. The terminology herein isused to describe specific embodiments of the invention, but their usagedoes not delimit the invention, except as outlined in the claims.

As used herein, a “cosmetic” refers to a substance that aids in theenhancement or protection of the appearance (e.g. color, texture, look,feel, etc.) or odor of a subject's skin. A cosmetic may change theunderlying structure of the skin.

A “skin disorder” refers to a disease or condition that affects thehealth of a subject's skin. In a preferred embodiment, the presentinvention comprises methods and compositions for the treatment ofconditions that affect skin care, which include but are in no waylimited to acne, bed sores, rash, dry skin, dermal abrasions,dermatitis, sunburn, scars, hyperkeratosis, granuloma and skinulceration.

Nanospun fiber diameters can range from 5 to 1000 nm; thereby adding anextremely high surface area to a polymeric surface but more importantlygiving the opportunity to combine unmixable polymers and drug cocktailsinto “semi-homogeneous” matrices with extreme volume containments. Nanospinning combines the process of using a high electric force generatedbetween capillary tips dispensing a polar polymer solution drawn towardsthe other pole, the receiver. The fiber diameter and the spun matrixporosity can be controlled by regulating the voltage, solution andsolvent composition together with humidity, temperature and pressure inthe environment of the process.

As used herein, the term “microfibers” refers to a fiber with a diameterin microns (e.g. 1 to 20 microns, but more typically betweenapproximately 5 and 10 microns). The term “nanofiber” refers to a fiberwith a diameter of less than 100 nanometers. In a preferred embodiment,said microfibers or nanofibers are produced via electrospinning, aprocess in which an electrical charge is used to generate a mat of saidfibers as described in Li et al. Advanced Materials 16, 1151-1170(2004), and by Smith in U.S. Pat. No. 6,753,454, hereby incorporated byreference. Electrospinning generally involves the introduction of apolymer or other fiber-forming liquid into an electric field, so thatthe liquid is caused to produce fibers. These fibers are drawn to anelectrode at a lower electrical potential for collection. During thedrawing of the liquid, the fibers rapidly harden and/or dry. Thehardening/drying of the fibers may be caused by cooling of the liquid,i.e., where the liquid is normally a solid at room temperature; byevaporation of a solvent, e.g., by dehydration (physically inducedhardening); by a curing mechanism (chemically induced hardening); or bya combination of these methods. Electrostatically spun fibers can beproduced having very thin diameters.

As can be understood the nano spinning process makes it possible tocreate a matrix with a variety of ingredients that are either a)contained into a matrix of fibers either as suspended particles,spheres, or free fluid between the fibers, b) particles, spheres or freefluid incorporated or coated into the bulk of the fiber from a mixedsolution, or c) allowed to fill hollow fibers made by concentriccapillary dispenser tips. The process runs at room temperature with norisk for harming the chemistry by heat. The solvents are selected withthe view on whether to dilute oil or water into the spinning solutionwhich also can draw fibers at a voltage lower than 1 KV/cm between thedispenser tip to the receiver. The charge will not harm to thechemistry.

The term “hydrophobic” refers to the physical property of a moleculethat is repelled from a mass of water. In a preferred embodiment,hydrophobic polymers are incorporated into the compositions of thepresent invention. While not limited to any particular polymer, examplesof hydrophobic polymers include PolyCarbothane (aliphatic,polycarbonate-based TPU), Shore A 75 through Shore D 72 (manufactured byThermedics Polymer Products, Wilmington, Mass.), Poly(Vinyl Acetate),PolySulfone (manufactured by Solvay Advanced Polymers Gmbh DusseldorfGermany), Poly(Vinyl Chloride) and biodegradable Polylactide (PLA)manufactured by Boehringer Ingelheim GmbH, Ingelheim Germany).

“Hydrophilic” refers to the physical property of a molecule that is ableto transiently associate with water (e.g. bond with water via hydrogenbonding). In a preferred embodiment, hydrophilic polymers areincorporated into the compositions of the present invention. While notlimited to any particular polymer, examples of hydrophilic polymersinclude Poly(Ethylene Glycol), Poly(Propylene Glycol), Poly(VinylAlcohol), Polypyrrolidone or Polyvinylpyrrolidone (PVP), and thebiodegradable PolyActive (a soft poly ethylene glycol-terephalate blockcopolymer with a hard poly butylene-terephthalate) manufactured byOctoPlus Zernikedreef Holland. In a preferred embodiment, PVP is ofsufficient molecular weight for electrospinning [Sigma #81440 K 90, molwt ˜360,000 (Fluka)].

A “solvent” is a liquid that dissolves a solid, liquid or gaseoussolute, generating a solution. Solvents may include but are in no waylimited to water and organic solvents including but not limited tochloroform (CHF), isopropanol (IPA), methanol (MEA), acetone andtetrahydrofuran (THF).

As used herein, the terms “prevent” and “preventing” include theprevention of the recurrence, spread or onset of a disease or disorder.It is not intended that the present invention be limited to completeprevention. In some embodiments, the onset is delayed, or the severityof the disease or disorder is reduced.

As used herein, the terms “treat” and “treating” are not limited to thecase where the subject (e.g. patient) is cured and the disease iseradicated. Rather, the present invention also contemplates treatmentthat merely reduces symptoms, improves (to some degree) and/or delaysdisease progression. It is not intended that the present invention belimited to instances wherein a disease or affliction is cured. It issufficient that symptoms are reduced.

“Subject” refers to any mammal, preferably a human (whether healthy ornot, whether a patient or not), livestock, or domestic pet.

As used herein, the term “topical” refers to administration of an agentor agents (e.g. cosmetic, medication, vitamin, etc.) on the skin.“Transdermal” refers to the delivery of an agent (e.g. cosmetic,medication, vitamin, etc.) through the skin (e.g. so that at least someportion of the population of molecules reaches underlying layers of theskin). It is not intended that the medication be limited to medicantsthat are delivered solely to the bloodstream, the medicant may betargeted, for example, to the skin or a subcutaneous area of a subject'sskin. “Between tissues” refer to surgical interventions where an agentin a biodegradable dressing (e.g. medication) is applied to stopbleeding, leakage, unwanted adhesion between organs or cell disorders inconnection anastomotic vascular bypass, implanted prostheses, or organsand cancer. In preferred embodiments, a specific dosage is delivered toand/or through the skin, or subcutaneously by surgical intervention. Inone embodiment, the present invention contemplates self-dissolvingpatches/sheets to be placed onto organs in open surgeries for fasterhealing and delivery of drugs (during surgery or post-closure). This canbe extended onto ophthalmic drug delivery where there is a need for anadhesiveness onto the wet surface of mucosa; the polymer formulationsdescribed herein can provide adhesion to such surfaces.

A “biomaterial” refers to a material that is produced by a livingorganism. It is not intended that the present invention be limited tomaterials that are produced by an organism per se, i.e. the presentinvention may comprise synthetic polymers that are inspired or wereoriginally identified in organisms or biological settings. Examples ofbiomaterials include but are in no way limited to starches, collagen,cellulose, algenates, sugars, proteins, peptides and nucleic acids.Preferably, the biomaterial is used in dry form (e.g. free-driedcollagen) during the manufacturing process for the composition. In oneembodiment, the present invention contemplates utilizing compounds andcompositions that stimulate collagen formation in the skin, includingtretinoin (all-trans retinoic acid) and peptides such as hexapeptide 14and the like. In one embodiment, Granactive Powder 168 (available fromGrant Industries, Inc., New Jersey, USA), a powdered anti-aging complexthat combines the matrix-fibroblast stimulation and collagen growth ofpalmitoyl hexapeptide-14 with plant derived fulvic acid (peat extract),is employed in the fiber matrices described herein to maximize therestorative powers of the skin's extra-cellular matrix (it also includes24 carat colloidal gold to facilitate the electrolytic transfer betweentrace minerals and the skin's natural metallic-based electrolytes).

In a specific embodiment, the term “pharmaceutically acceptable” meansapproved by a regulatory agency of the federal or a state government orlisted in the U.S. Pharmacopeia or other generally recognizedpharmacopeia for use in animals, and more particularly in humans. Theterm “carrier” refers to a diluent, adjuvant, excipient or vehicle withwhich the active compound is administered. Such pharmaceutical vehiclescan be liquids, such as water and oils, including those of petroleum,animal, vegetable or synthetic origin, such as peanut oil, soybean oil,mineral oil, sesame oil and the like. In addition, auxiliary,stabilizing, thickening and coloring agents can be used. The presentcompositions, if desired, can also contain minor amounts of pH bufferingagents.

“Impregnated” means filled or added to, but need not be limited tosaturated conditions. Furthermore, it is not intended that the term belimited to encapsulation, although encapsulation is contemplated. In oneembodiment, the polymeric microfiber or nanofiber web is impregnated byintercalation of the active ingredient or ingredients into the voidspaces of said microfiber or nanofiber matrix (and/or into the fibersthemselves).

DETAILED DESCRIPTION OF THE INVENTION

The present invention relates to methods and compositions for thedelivery of agents, e.g. cosmetics and medicants. In some embodiments,the invention relates to compositions comprising both hydrophobic andhydrophilic polymers. In preferred embodiments, the invention relates tothe delivery of peptides, small molecules and other bioactive compoundsusing the compositions and methods disclosed herein. In furtherembodiments, the invention relates to compositions comprising clay andfurther comprising a bioactive agent for the treatment of skin diseasesand disorders.

In some embodiments, the invention relates to compositions that areimpregnated with one or more active agents in dry form, or with asolution of one or more active ingredients for the controlled orsustained delivery of said active ingredients. Bioresorbable materialsdesigned for the delivery of medicants and active agent delivery haspreviously been described as provided for in US Patent ApplicationNumber 2007/0213522 to Harris et al., incorporated herein by reference.

In some embodiments, the invention relates to the topical or transdermaldelivery of a medicant for the purpose of treating a disease. The use ofcontrolled-release skin patch delivery platforms have been previouslydescribed in U.S. Pat. No. 6,352,715 to Hwang et al., incorporatedherein by reference.

In a preferred embodiment, the invention comprises a hydrophilicpolymer. The polymer is selected such that it may dissolve inpreparatory solvents, which include but are in no way limited toethanol, isopropanol (IPA), methanol (MEA), acetone and tetrahydrofuran(THF). The solvent or solvents may further be used to dissolve activeingredients, providing a heterogeneous mixture of the polymer and theactive ingredient. In a preferred embodiment, said active ingredientsare oil based. The resulting polymeric fibers may be segmented intocompositions comprising said active ingredients and said hydrophilicpolymers and dried such that a microfiber or nanofiber is obtained. Thepolymer has the further ability to coat and encapsulate the(hydrophilic) dried particles.

In a preferred embodiment, the invention comprises a hydrophobicpolymer. The polymer is selected for its tensile strength and stiffnesssuch that it will keep the matrix in a stable form even when thehydrophilic polymer absorbs moisture, expands and applies stress to theintegrated microfiber or nanofiber matrix. The stiffness and volume ofthe hydrophobic fiber further imparts flexibility and handling strengthto the invention.

In a preferred embodiment, the present invention contemplates amicrofiber or nanofiber web with two components: hydrophobic polymer isused as “structural”, backbone, while a hydrophilic component is used to“encapsulate” the active ingredients. While not intended to limit thepresent invention to any particular mechanism, it is believed that, asthe water enters the microfiber or nanofiber web, the hydrophobicstructure remains intact. At the same time water “attacks” thehydrophilic branches and replaces the active ingredients—providing arelease mechanism for the active agent. In one embodiment, the presentinvention contemplates a method of manufacture, wherein said twocomponents are electrospun so as to create the polymeric microfibers ornanofibers.

In one embodiment, the present invention contemplates self-dissolving(i.e. upon application to the skin, and in particular, moist skin, itdissolves without the need for further manipulations, solvents or otherchemicals) transdermal device comprises a homogeneous polymeric matrixor a heterogeneous polymeric matrix, all of which or sections of whichare optimized to carry specific functions for the final product (patchor plaster). In one embodiment, the uppermost section of the patchfeatures chemical properties to enable occlusive or non-occlusiveenvironment under the patch. In one embodiment, intermediate patchlayers (see FIG. 5) contain active agents that are incorporated into thestructural backbone of the polymer or into the voids of the structure,which allows for control over release rate of active agents out of thematrix. In one embodiment, the bottom section of the patch secures thedevice to a surface (skin) provided by adhesive properties of thepolymer used in segments of the bottom section of the device.

Enhancing Delivery

As noted above, the films and patches of the present invention can beused alone or with other modes of delivery, including but not limited todelivery enhancing compounds, microneedles, iontophoresis,electroporation, and the like. In another embodiment, the film or patchis part of an iontophoresis patch. Each of these approaches is discussedmore below.

A. Delivery Enhancing Compounds

An optional enhancer may be combined with the films and patchesdescribed herein (or may be optionally applied to the skin prior to theapplication of the film or patch). It may be added to the polymermixture during the optional blending step, or more preferably during orprior to the electrospinning step. The choice of enhancer to beoptionally incorporated in the transdermal drug delivery matrix willdepend upon the polymer and active agent to be administered. Suitableenhancers for use in this invention include, but are not limited to,dimethylsulfoxide (DMSO), dimethylformamide (DMF), N,N-dimethylacetamide (DMA), decylmethylsulfoxide (CloMSO), polyethyleneglycol monolaurate (PEGML), propylene glycol (PG), propylene glycolmonolaurate (PGML), methyl laurate, lauryl alcohol, glycerolmonolaurate, linoleic acid, oleic acid, oleic acid dimers, oleylalcohol, glycerol mono-oleate, glycerol dioleate, glycerol trioleate,lauryl lactate, myristyl lactate, sorbitan monolaurate, sorbitanmono-oleate, lauramide diethanolamide, lecithin, the 1-substitutedazacycloheptan-2-ones (preferably 1-n-dodecylcyclazacycloheptan-2-one,available under the trademark Azone (from Whitby Research Inc.,Richmond, Va.), alcohols, lactate esters of C12 to C18 aliphaticalcohols, and the like. The permeation enhancer may also be a vegetableoil, as described in U.S. Pat. No. 5,229,130 to Sharma et al. Such oilsinclude, by way of example and not for purposes of limitation, saffloweroil, cotton seed oil and corn oil. In addition, combinations ofenhancers as enumerated above, or as described in U.S. Pat. No.5,053,227 to Chiang et al. and U.S. Pat. No. 5,693,335 to Xia et al.,both of which are hereby incorporated by reference, may be used in thepresent invention.

The amount of enhancer present in the composition will depend on anumber of factors, e.g. the strength of the particular enhancer, thedesired increase in skin permeability, the rate of administration, andthe type and amount of active agent to be delivered. The enhancedpermeation effected through the use of such enhancers can be observed bymeasuring the rate of diffusion of active agent through animal or humanskin using a Franz diffusion cell apparatus as described in U.S. Pat.No. 5,807,570 to Chen et al., hereby incorporated by reference. Suchdeterminations are easily made by one of ordinary skill in the art (see,for example, Volume 62 of Drugs and the Pharmaceutical Sciences,entitled “Drug Permeation Enhancement: Theory and Applications” (1994)Marcel Dekker, Inc.).

B. Microneedles

In one embodiment, microneedles (discussed more below) are applied tothe skin in the way that the film or patch is placed on top of themicroneedles (which may be pre-treated to facilitate the dissolution ofthe patch and release of active ingredients) so that compounds(including high molecular weight compounds) are delivered more readily(and more deeply) into the skin. It is not intended that the presentinvention be limited to a particular microneedle design or product. Anexample is disclosed in U.S. Pat. No. 3,964,482 (by Gerstel), in whichan array of either solid or hollow microneedles is used to penetratethrough the stratum corneum, into the epidermal layer.

C. Iontophoresis

Iontophoresis is a non-invasive method of propelling high concentrationsof a charged substance, normally medication or bioactive agents,transdermally by repulsive electromotive force using a small electricalcharge applied to an iontophoretic chamber containing a similarlycharged active agent and its vehicle. Iontophoresis performs desiredmedical treatment by driving (carrying) an ionizable or ionic drug,which has been applied on the skin, under predetermined electromotiveforce to deliver the same into the skin. For example, positively chargedions are driven (carried) into the skin on the side of an anode in anelectric system of an iontophoresis device. Negatively charged ions, onthe other hand, are driven (carried) into the skin on the side of acathode in the electric system of the iontophoresis device.Iontophoresis is well classified for use in transdermal drug delivery.Unlike transdermal patches, this method relies on active transportationwithin an electric field. In the presence of an electric fieldelectromigration and electroosmosis are the dominant forces in masstransport. These movements are measured in units of chemical flux.

A number of vitamins are negatively chargeable (hereinafter abbreviatedas V) (VB₂, VB₁₂, VC, VE, folic acid, etc.). Some antibiotics are alsonegatively chargeable (penicillins water soluble drugs, chloramphenicolwater soluble drugs).

Pharmaceutical Formulations

The present compositions can take the form of sustained-releaseformulations. In one embodiment, the pharmaceutically acceptable vehicleis a capsule (see e.g., U.S. Pat. No. 5,698,155). For example, in oneembodiment, encapsulated vitamins are employed, including but notlimited to encapsulated vitamin C available from Nanohybrid Co. (Seoul,Korea).

In a preferred embodiment, the active compound or compounds incorporatedinto the polymeric microfibers or nanofibers may be manipulated so as toform a solution of the active ingredient or ingredients in the nanofiberfor controlled or sustained delivery of the active ingredient oringredients. In some embodiments, said active ingredient or ingredientsare activated upon wetting of the composition. Where necessary, thecompositions can also include a solubilizing agent. Generally, theingredients are mixed together in unit dosage form. In one embodiment,the unit dosage form is administered through an epicutaneously-appliedcomposition.

Further, the effect of the active compound(s) can be delayed orprolonged by proper formulation. Compositions for use in accordance withthe present invention can be formulated in conventional manner using oneor more physiologically acceptable carriers or excipients. Thus, thecompound and optionally another therapeutic or prophylactic agent andtheir physiologically acceptable salts and solvates can be formulatedinto pharmaceutical compositions for administration by topical ortransdermal administration.

In certain preferred embodiments, the composition contains one or moreunit dosage forms containing no more than the recommended dosageformulation as determined in the Physician's Desk Reference (62^(nd) ed.2008, herein incorporated by reference in its entirety).

Methods of administering the active compound and optionally anothertherapeutic or prophylactic agent are topical or transdermal.Administration can be local or systemic.

In specific embodiments, it can be desirable to administer the activecompound locally to the area in need of treatment. This can be achieved,for example, and not by way of limitation, by local infusion topicalapplication, e.g., in conjunction with a wound dressing after surgery.In one embodiment, the fiber matrices described herein can be applied towounds as a film. Such matrices may include compounds that promote woundhealing, such as propranolol or nitric oxide (which are useful to treatburns). In one embodiment, these compounds are encapsulated (e.g. innanospheres which dissolve upon contact with an aqueous environment,including moist skin). Such matrices may include peptides that recruitcells to heal wounds, such as PHSRN as described in U.S. Pat. No.6,025,150, hereby incorporated by reference. In another embodiment,laminin-111 peptides, A13 and C16, from the laminin alpha1 and gamma1chain, respectively, are employed to promote wound healing. In someembodiments, it may be useful to apply non-dissolving or very slowdissolving films or patches so that the wound or burn is covered andprotected for a desired time period.

The amount of the active compound that is effective in the treatment orprevention of skin diseases or disorders can be determined by standardresearch techniques. For example, the dosage of the active compoundwhich will be effective in the treatment or prevention of a skincondition or disorder can be determined by administering the activecompound to an animal in a model such as, e.g., the animal models knownto those skilled in the art. In addition, in vitro assays can optionallybe employed to help identify optimal dosage ranges.

Selection of a particular effective dose can be determined (e.g., viaclinical trials) by a skilled artisan based upon the consideration ofseveral factors, which will be known to one skilled in the art. Suchfactors include the disease to be treated or prevented, the symptomsinvolved, the subject's body mass, the subject's immune status and otherfactors known by the skilled artisan.

The dose of the active compound to be administered to a subject, such asa human, is rather widely variable and can be subject to independentjudgment. It may be practical to administer the daily dose of the activecompound at various hours of the day. However, in any given case, theamount of the active compound administered will depend on such factorsas the solubility of the active component, the formulation used, andsubject condition, for example, said subject's weight.

EXAMPLES

The following examples are provided in order to demonstrate and furtherillustrate certain preferred embodiments and aspects of the presentinvention and are not to be construed as limiting the scope thereof.

Example I

In a typical application, one selects an agent or agents for topicaladministration to a subject. In a preferred embodiment, said agent oragents are active ingredients that are targeted against a specific skincondition. In further embodiments, said agent or agents are a cosmetic.One or more dry active ingredients including but not limited to acosmetic, peptide, vitamin, organic acid, oil or medicant areincorporated into a microfiber or nanofiber matrix via electrospinning.Further addition of the active ingredient or ingredients is achieved viaintercalation of said active ingredient or ingredients into the voidspaces of said microfiber or nanofiber matrix. A biopolymer includingbut in no way limited to collagen, cellulose or an algenate isimpregnated with a solvent delivery system, i.e. a liquid. The solvateddelivery biopolymer is then combined with the activeingredient-containing microfiber (or nanofiber) matrix to form oneembodiment of the present invention.

Example II

In this example, a film or “patch” media is described based on a matrixhaving a hydrophilic fiber co-spun with a hydrophobic fiber. In thisexample, the hydrophilic polymer is either TECOGEL® 500 or TECOGEL®2000. In this example, the hydrophobic polymer is either Carbothane3575D or PolySulfone UDEL P3500NT (PolyCarbothane is available fromLubrizol, PolySulfone is available from Solvay). The hydrophilic fibercontains the chemistry (i.e. active ingredient) which will be eluted (orforced) out of the matrix when water is added (while not limited to anyparticular mechanism, it is believed that this is due to hydrophobicfibers inability to enlarge i.e. make additional volume in the matrix).The dosage delivered per unit time can be adjusted by proportionallychanging the amount of hydrophilic versus hydrophobic polymer in thismedia. This patch media is developed under the name, Control ActivityManager, or CAM.

To fabricate the matrix, the hydrophilic and hydrophobic polymers areco-spun (electrospun as described above). More specifically, 4 mls ofthe PolySulfone solution (UDEL-P-3500+CHF+MEA) is co-spun with 20 ml“active” TG-2000 solution, (TG-2000+THF+MEA/Ethanol). The 20 ml “active”solution is a mix of:

1. 5 ml of TG-2000 solution.

2. 5 ml of TG-2000 solution+0.033 g low MW HA

3. 5 ml of TG-2000 solution+1.4 g GrantActive 168

4. 5 ml of TG-2000 solution+0.165 g Olive Oil

The mix is done as follows: solutions 1+2+3 are added together to make a15 mls solution; thereafter solution number 4 is added on top.Importantly, For solutions 1, 2 and 4, the TG solution is a mix ofTecoGel 2000+THF+MEA. For solution number 3, the TG solution is a mixof: TecoGel 2000+THF+Ethanol (GrantActive 168 is water based so the MEAshould be replaced by ethanol. The resulting media reacts with humidskin, it has a relatively slow dissolution rate.

Alternatively, active ingredients can be encapsulated in nanospheres,which can then be formulated into a CAM matrix by adding the nanospheresto the solution.

Example III

In this example, a film or “patch” media is described based on a matrixhaving only hydrophilic fibers produced from a fully water dissolvablepolymer, such as PVP (Polyvinylpyrrolidone). This patch media isdeveloped under the name, the Disappearing patch DISL.

To fabricate the matrix, the polymer is electrospun. The processparameters for nano electro spinning of the DISL patch are as follows:

Distance from tip to collector: 25 cm

Electric field at tip: −20 KV

Electric field at collector: +6 KV

Tip geometry: 18 gauge

Flow rate: 40 ml/h

Temperature: +22 Celsius

Humidity: 60% RH

One example of a formulation of a DISL patch solution with an activeingredient (e.g. a stable form of vitamin C) along with additional(optional) ingredients includes:

Base 5 ml Mixed of:

-   -   1. 25 g 11% PVP K90 solution (PVP K90+MEA+Ethanol)    -   2. 0.4 g VitaC hydrophobic (CNG G25)    -   3. 0.3 g HyaCare® 50 low MW Hyaluronic acid (while not limited        to any particular mechanism, it is believed that HA because of        its charge draws water into the structure)    -   4. 0.2 g Buthylene Glycol        Top 5 ml Mixed of:    -   5. 25 g 11% PVP K90 solution (PVP K90+MEA+THF)    -   6. 3.8 g Olive Oil    -   7. 1.4 g Retinol Fluid [the pinacolyl ester of all-trans        retinoic acid (tretinoin), available from Grant Industries,        Inc.]    -   8. Fragrance        Since Buthylene Glycol is water based, ethanol is used in the        PVP K90 solution (see number 1, above). On the other hand, since        Retinol Fluid is oil based, methanol is used in the PVP K90        solution (see number 5, above). This media instantly dissolves        upon contact with moist skin and thereby delivers the active        ingredients.

Alternatively, active ingredients can be encapsulated in nanospheres,which can then be formulated into a DISL matrix by adding thenanospheres to the solution.

Example IV

In this example, a film or “Biodegradable Dressing” media is describedbased on a matrix having three layers gradually changed from firsthydrophilic layer incorporating Thrombin (such as RECOTHROM™manufactured by Zymogenetic Inc or Tisseel a two component fibrinbiomatrix manufactured by Baxter Inc) to a second hydrophobic layercreating a barrier preventing the Thrombin to migrate into third layercontaining High molecular weight of Hyaluronic Acid. This patch media isdeveloped as a combined Hemostate and anti-adhesion membrane.

To fabricate the matrix, three layers are electrospun from threedifferent solutions via three tips on to one and same collector. Theprocess begins by adding the first layer to the collector, thencontinuing with adding the first combined with second layer, thengradually removing the first layer while continuing with a second layeralone, then continuing with a combined second and third layer, thengradually removing the second layer and continuing with a third layer.Each layer originates from its specific solution spun by its dedicatedtip. One example of formulation for a combined Hemostate andanti-adhesion membrane includes: First solution (5 g PolyActive+24 gCHF+2 g Aceton+Thrombin was added to an amount of 47.5 IU/cm²); Secondsolution (5 g PLA+24 g CHF+2 g MEA); Third solution (5 g PLA+24 g CHF+2g MEA+0.1 g HA). The membrane showed haemostatic effect when applied toa blood oozing animal liver tissue and the HA eluted slowly giving agreasy surface.

Example V

In this example, one embodiment of an “on command” delivery approach isdescribed. While nicotine is used in this example, the present inventioncontemplates “on command” with a variety of different activeingredients.

Nicotine “on command” delivery:

1) A sphere made by water dissolvable material like silica contains highconcentration nicotine.

2) Those spheres containing nicotine are trapped within a “semihydrophilic” matrix, originating from a solvent based solution.

3) The “sphere matrix” is placed as an ordinary nicotine plaster elutinga uniform dose through the skin over the day.

4) When the subject/patient feels a “sudden hunger for a smoke” he canwet the plaster (in whole or in part) in order to get a bolus dose oncommand.

Although the invention has been described with specific embodiments, itshould be understood that the invention as claimed should not be undulylimited to such specific embodiments.

We claim:
 1. A method for delivering an active ingredient into the skin,comprising: a) providing i) a subject, ii) a solution comprising anactive ingredient; iii) a skin patch comprising electrospun hydrophilicfibers; b) pre-wetting the skin of said subject with said solution; andc) administering said skin patch to said subject under conditions suchthat said active ingredient is delivered into the skin, and said patchforms an invisible film that dissolves completely in less than oneminute of wetting with said solution.
 2. The method of claim 1, whereinsaid pre-wetting comprises spraying said solution onto said skin.
 3. Themethod of claim 2, wherein said spraying results in a mist or aerosol.4. The method of claim 1, wherein the active ingredient is selected fromthe group consisting of a cosmetic, peptide, vitamin, organic acid, oil,drug or medicant.
 5. The method of claim 4, wherein said activeingredient is a vitamin.
 6. The method of claim 5, wherein said vitaminis selected from the group consisting of vitamin C, vitamin A, vitaminE, vitamin K and vitamin B complex.
 7. The method of claim 4, whereinsaid active ingredient is an organic acid.
 8. The method of claim 7,wherein said organic acid is hyaluronic acid.
 9. The method of claim 1,wherein said skin patch lacks hydrophobic fibers.
 10. The method ofclaim 4, wherein said active ingredient is a cosmetic.
 11. The method ofclaim 10, wherein said cosmetic is botulinum toxin.
 12. The method ofclaim 1, wherein said subject exhibits symptoms associated with a skindisorder.
 13. The method of claim 12, wherein said skin disorder isselected from the group consisting of acne, bed sores, rash, dry skin,dermal abrasions, dermatitis, sunburn, scars, hyperkeratosis, granulomaand skin ulceration.
 14. The method of claim 4, wherein said activeingredient is a drug.
 15. The method of claim 14, wherein said drug isdiclofenac.
 16. The method of claim 4, wherein said active ingredient isa medicant.
 17. The method of claim 16, wherein said medicant istretinoin.